Clinical meaning
Cognitive decline encompasses a spectrum from subjective cognitive complaints to mild cognitive impairment (MCI) to dementia. Alzheimer disease (most common) involves extracellular amyloid-beta plaque deposition, intracellular neurofibrillary tangles (hyperphosphorylated tau protein), synaptic loss, and cholinergic neuron degeneration in the hippocampus and association cortices. Vascular cognitive impairment results from chronic cerebrovascular disease (white matter lesions, lacunar infarcts). Lewy body dementia involves alpha-synuclein aggregates causing fluctuating cognition, visual hallucinations, and parkinsonism. Frontotemporal dementia involves tau or TDP-43 protein aggregates causing personality changes and language deficits. Reversible causes (vitamin B12 deficiency, hypothyroidism, normal pressure hydrocephalus, medication effects, depression) must be excluded before diagnosing neurodegenerative disease.